A statistical model of ChIA-PET data for accurate detection of chromatin 3D interactions.
Identification of three-dimensional (3D) interactions between regulatory elements across the genome is crucial to unravel the complex regulatory machinery that orchestrates proliferation and differentiation of cells. ChIA-PET is a novel method to identify such interactions, where physical contacts between regions bound by a specific protein are quantified using next-generation sequencing. However, determining the significance of the observed interaction frequencies in such datasets is challenging, and few methods have been proposed. Despite the fact that regions that are close in linear genomic distance have a much higher tendency to interact by chance, no methods to date are capable of taking such dependency into account. Here, we propose a statistical model taking into account the genomic distance relationship, as well as the general propensity of anchors to be involved in contacts overall. Using both real and simulated data, we show that the previously proposed statistical test, based on Fisher's exact test, leads to invalid results when data are dependent on genomic distance. We also evaluate our method on previously validated cell-line specific and constitutive 3D interactions, and show that relevant interactions are significant, while avoiding over-estimating the significance of short nearby interactions.


d-Dimensional (d >/= 3) shuffle interconnections.
The need for d-dimensional (d >/= 3) interconnection patterns occurs if d-dimensional data cubes have to be interconnected. The formal definition of such patterns, presented here, is based on the mixed radix numbering of the d-tuple data points. Because each coordinate of a d-dimensional data cube may be factorized in a different way, a family of interconnection patterns is obtained that increases with respect to the dimension of the data cubes. The properties of d-dimensional patterns are analyzed, and their realization in the frequency domain is described. Methods for the three-dimensional layout of the patterns are presented. The application of d-dimensional patterns within multistage interconnection networks is discussed.


Utility of International Classification of Functioning, Disability and Health's participation dimension in assigning ICF codes to items from extant rating instruments.
Firstly to investigate the utility of the International Classification of Functioning, Disability and Health's (ICF's) participation dimension when items from extant questionnaires focusing on participation were assigned to ICF codes on an item-by-item basis; and, secondly, to conduct a preliminary investigation of the theoretical assumption expressed in ICF that ICF's environment component interacts with body function and participation components. A person-based, descriptive study. The sample comprised students with disabilities (n = 448), their parents/relatives (n = 414), their teachers/managers (n = 418) and special education consultants (n = 110). Items from original surveys were used. Participation of students with disabilities: a survey of participation in school activities, The Arc's Self-Determination Scale, Perceived interaction-questionnaire, Environments survey, The Abilities Index. Data were analysed with the help of ANOVA, Scheffé pair-wise comparisons, correlation analysis and cluster analysis. The study partly confirmed the utility of ICF participation dimension in assigning codes to items from extant instruments. Moderate statistical correlations between participation chapters and between items from different ICF dimensions were found. Cluster analysis resulted in groups with participation patterns not related to type of disability. Items from extant instruments can be assigned to ICF participation codes, but further item analyses and a more extensive questionnaire base are needed.


Interstitial inflammation in Alport syndrome.
The Alport syndrome is a hereditary glomerular disease linked to structural abnormalities of collagen IV. In a mouse model of Alport syndrome, the interstitial lymphocyte influx was important for disease progression. CXCR3 is a chemokine receptor involved in lymphocyte recruitment to the kidney. We hypothesized that CXCR3-positive T cells might be involved in human Alport syndrome. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded biopsies from 17 patients with Alport syndrome, 10 with immunoglobulin A (IgA) nephropathy, and 11 healthy donor kidneys. We investigated the expression of the alpha5 chain of collagen IV to confirm the morphologic diagnosis, the chemokine receptor CXCR3 and CD3-positive T cells. Alport syndrome biopsies demonstrated a complete loss of the alpha5 chain of collagen IV from the glomerular basement membrane and the morphologic features consistent with Alport syndrome on electron microscopy. A prominent number of CXCR3-positive cells were found in the tubulointerstitium. Most of the CXCR3-positive cells were CD3-positive T cells, demonstrated by double-labeling in selected biopsies. The number of CXCR3-positive cells in kidneys with Alport syndrome correlated with serum creatinine (P < .05) and with morphologic features of a progressive disease (eg, interstitial fibrosis, glomerulosclerosis, and tubular atrophy). The severity of interstitial CXCR3-positive cell influx was similar in Alport syndrome as compared to immunoglobulin A nephropathy. The noninflammatory glomerular lesion of Alport syndrome is associated with prominent interstitial accumulation of CD3- and CXCR3-positive lymphocytes. The degree of infiltration correlated with renal function. We speculate that targeting T lymphocytes, for example, by CXCR3 blocking agents, might be a novel approach to inhibit disease progression in patients with Alport syndrome.


A sensitive immunochemical assay for measuring the concentration of the activated protein C-protein C inhibitor complex in plasma: use of a catcher antibody specific for the complexed/cleaved form of the inhibitor.
Activated protein C (APC) is a serine proteinase that regulates blood coagulation. In plasma it is inhibited mainly by the protein C inhibitor (PCI). The plasma concentrations of APC-PCI complex is increased in hypercoagulative states such as deep venous thrombosis. Formation of the APC-PCI complex induces a drastic conformational change in PCI that exposes new epitopes (neoepitopes) on the molecule. We have devised a simple immunofluorometric sandwich assay for measurements of the concentrations of APC-PCI complex, employing as the catcher, a monoclonal antibody that has a high affinity (K(D) = 4 x 10(-11) M) for a complexation-specific neoepitope that is expressed on PCI. A monoclonal antibody against protein C is employed as the tracer. The method gives a linear dose-response curve (0.06-50 microg/l), has a low detection limit (0.06 microg/l) and no crossreactivity with native PCI at physiologic plasma concentrations. We have now determined the concentration of the APC-PCI complex in healthy individuals.


[Percutaneous transcatheter valve therapy].
Aortic stenosis (AS) and mitral regurgitation (MR) are currently the commonest valvular pathologies in developed society. The current standard of treatment of severe AS and severe MR has been surgical aortic valve replacement (AVR) and mitral valve (MV) surgery. In 2002, the first human percutaneous AVR (PAVR) was performed and in 2005, results of percutaneous MV repair were also reported. The field of percutaneous transcatheter valve therapy is evolving very rapidly. There are 2 aortic percutaneous heart valves in clinical trials and several others with first-in-man data or in pre-clinical testing. Results seem promising and it appears that PAVR will most likely be a viable option for selected patients in a relatively short time. The future of AS treatment will evolve with the advent of devices which will be repositionable and retrievable, as well as integrating other materials engineered by nanotechnology and tissue engineering. There are several technologies being investigated in the field of MV repair, each attempting to mimic surgical technique. Compared with PAVR, percutaneous MV repair is a more complex process as many different pathological processes can result in MR. The current technologies will be suitable only for carefully selected patients with a specific etiology of MR. Most likely a combination of these technologies will be required for satisfactory MV repair although MV replacement may be what many of those patients require, and therefore percutaneous MV replacement will be an exciting alternative in the near future.


The effect of plasmapheresis on blood pressure in voluntary plasma donors.
Donor plasmapheresis involves the removal of a weight-adjusted volume of plasma and the return of cellular components to the donor. Although plasma volume generally returns to normal, some residual effect on vital signs may be possible. This analysis was performed to determine the possible effects of plasmapheresis on blood pressure. A 16-week study was conducted to evaluate the effects of plasma donations on cholesterol levels in healthy donors. From this study, the vital signs obtained prior to donation were analysed using statistical and dynamic analytical predictive models. Preliminary analyses revealed a change in systolic and diastolic blood pressure from the corresponding baseline values (Pearson Coefficient -0.44 and -0.47, respectively). Statistical models predicted a marked decrease in systolic and diastolic blood pressure following multiple donations in donors with baseline pressure in the Stage 2 hypertension range with less pronounced decreases predicted in Stage 1 donors. Little or no change in blood pressure was predicted in donors with baseline normal blood pressure or prehypertension. Dynamic models including time between donations supported these results and predicted a recovery period of about 14 days without donation in donors with Stage 2 baseline levels. Results suggest that systolic and diastolic blood pressure may be decreased following plasmapheresis used for plasma donations at intervals of <14 days in donors with high baseline blood pressure levels.


Trajectories of overweight and their association with adolescent depressive symptoms.
To explore the potential for a developmental approach to reveal new insights into the well-documented link between weight and depressive symptoms. Latent class analysis identified multiple trajectories of overweight from 24 months to 15 years in the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (n = 957). Structural equation models then used these classes to predict depressive symptoms at age 15. Five latent classes captured continuity and change in weight from early childhood into middle adolescence. Controlling for current weight, stably overweight girls tended to have the most depressive symptoms, but popularity and positive image appeared to buffer against some of the risks that girls faced from being stably overweight or becoming overweight in early to middle childhood. Notably, boys' longitudinal weight patterns were not associated with their depressive symptoms in adolescence. Weight histories, controlling for current weight, are important for understanding the psychological experience of overweight, especially when such histories are considered in relation to other aspects of psychosocial functioning. (PsycINFO Database Record


Low-level laser therapy decreases renal interstitial fibrosis.
the purpose of this study was to investigate the effect of low-level laser therapy (LLLT) on chronic kidney disease (CKD) in a model of unilateral ureteral obstruction (UUO). Regardless of the etiology, CKD involves progressive widespread tissue fibrosis, tubular atrophy, and loss of kidney function. This process also occurs in kidney allograft. At present, effective therapies for this condition are lacking. We investigated the effects of LLLT on the interstitial fibrosis that occurs after experimental UUO in rats. The occluded kidney of half of the 32 Wistar rats that underwent UUO received a single intraoperative dose of LLLT (AlGaAs laser, 780 nm, 22.5 J/cm(2), 30 mW, 0.75 W/cm(2), 30 sec on each of nine points). After 14 days, renal fibrosis was assessed by Sirius red staining under polarized light. Immunohistochemical analyses quantitated the renal tissue cells that expressed fibroblast (FSP-1) and myofibroblast (α-SMA) markers. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to determine the mRNA expression of interleukin (IL)-6, monocyte chemotactic protein-1 (MCP-1), transforming growth factor (TGF)-β1 and Smad3. The UUO and LLLT animals had less fibrosis than the UUO animals, as well having decreased expression inflammatory and pro-fibrotic markers. For the first time, we showed that LLLT had a protective effect regarding renal interstitial fibrosis. It is conceivable that by attenuating inflammation, LLLT can prevent tubular activation and transdifferentiation, which are the two processes that mainly drive the renal fibrosis of the UUO model.


Changes in the extracellular matrix of the normal human breast during the menstrual cycle.
The normal human mammary gland undergoes a well defined sequence of histological changes in both epithelial and stromal compartments during the menstrual cycle. Studies in vitro have suggested that the extracellular matrix surrounding the individual cells plays a central role in modulating a wide variety of cellular events, including proliferation, differentiation and gene expression. We therefore investigated the distribution of a number of extracellular matrix molecules in the normal breast during the menstrual cycle. By use of indirect immunofluorescence, with specific antibodies, we demonstrated that laminin, heparan sulphate proteoglycan, type IV collagen, type V collagen, chondroitin sulphate and fibronectin undergo changes in distribution during the menstrual cycle, whereas collagen types I, III, VI and VII remain unchanged. These changes were most marked in the basement membrane, sub-basement membrane zone and delimiting layer of fibroblasts surrounding the ductules where basement membrane markers such as laminin, heparan sulphate proteoglycan, and type IV and V collagens appear greatly reduced during the mid-cycle period (days 8 to 22). These results suggest that some extracellular matrix molecules may act as mediators in the hormonal control of the mammary gland, whereas others may have a predominantly structural role.


Computed tomography scans as an objective measure of disease severity in chronic rhinosinusitis.
A truly objective method of measuring disease severity in chronic rhinosinusitis (CRS) has only recently existed. We evaluated computed tomography (CT) scans of CRS patients using this novel objective 3D computerized system and compared results with a novel 2D computerized analysis of a single coronal slice through the osteomeatal complex (OMC) and subjective methods including Lund-Mackay and Zinreich's modified Lund-Mackay. Prospective multicenter study. Two academic tertiary referral centers. Forty-six adults with a diagnosis of CRS underwent CT examination and received an intramuscular triamcinolone injection, dosage weight dependent, followed by CT scan 4 to 5 weeks later. Recruitment lasted 21 months. Scans were evaluated with all 4 scoring methods over 5 months. The Lin's concordance class correlation (CCC) of the OMC method revealed the best correlation to the 3D volumetric computerized values (0.915), followed by the Zinreich (0.904) and Lund-Mackay methods (0.824). Posttreatment results demonstrated that both the OMC (0.824) and Zinreich's (0.778) methods had strong agreement with the 3D volumetric methods and were very sensitive to change, whereas the Lund-Mackay (0.545) had only moderate agreement. Computerized CT analysis provides the most comprehensive, objective, and reproducible method of measuring disease severity and is very sensitive to change induced by treatment intervention. A 2D coronal image through the OMC provides a valid, user-friendly method of assessing CRS and is representative of CRS severity in all sinuses. Zinreich's subjective method correlated well overall, but the Lund-Mackay method lagged behind in disease representation and sensitivity to change.


Myeloma Is Not a Single Disease.
Treatment of plasma cell disorders has dramatically improved during the past decade as a result of the availability of new biology-based drugs, such as proteasome inhibitors and immunomodulatory agents. With increased attention to disease biology, however, it has become clear that there are many different subsets of patients with myeloma with different biologic drivers as well as different patient-based characteristics that can influence treatment. Obtaining initial genetics or genomics information can provide some of the information needed to define therapy after initial induction, and careful performance status assessment can help to define patient-specific characteristics that are important when determining the intensity of therapy. Careful assessment of both can help to optimize therapy type and duration for all patients and to improve long-term outcomes.


Lymphocyte subsets in children younger than 2 years old: normal values in a population at risk for human immunodeficiency virus infection and diagnostic and prognostic application to infected children.
Data were collected prospectively from 116 children younger than 2 years old who were seen at the Duke Pediatric AIDS Clinical Trials Unit for known human immunodeficiency virus seropositivity. Forty-six (40%) of these children were human immunodeficiency virus-infected and 70 were not infected. Using 3-month blocks, 10th, 50th and 90th percentiles were calculated for the CD4+ and CD8+ cell counts, percentage of lymphocytes positive for CD4 and CD8 and T4:T8 ratios. Results from the infected and uninfected children were compared. By 3 to 6 months of age the infected patients had significantly lower CD4+ counts, percentage CD4+ cells and T4:T8 ratios, whereas the percentage of CD8+ lymphocytes was significantly higher. Absolute CD8+ counts were approximately the same in infected and uninfected children through age 2 years. Most infected children had one or more abnormal lymphocyte subset results (less than the 10th percentile for uninfected patients) by age 2: 83% had an abnormal CD4+ percentage; 78% had an abnormal T4:T8 ratio; and 67% had an abnormal CD4+ count. All 13 children who had an opportunistic infection (at any age) had an abnormal CD4+ percentage before age 2 years, and 12 of 13 had a low absolute CD4+ count or T4:T8 ratio. Among patients who died 10 of 11 had 1 or more low CD4+ count, 9 of 11 had an abnormal CD4+ percentage and 8 of 11 an abnormal T4/T8 ratio.


A high-quality human reference panel reveals the complexity and distribution of genomic structural variants.
Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals.


Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy.
Pericyte loss is an early pathologic feature of diabetic retinopathy, consistently present in retinae of diabetic humans and animals. Because pericyte recruitment and endothelial cell survival are controlled, in part, by the angiopoietin/Tie2 ligand/receptor system, we studied the expression of angiopoietin-2 and -1 in relation to the evolution of pericyte loss in diabetic rat retinae, using quantitative retinal morphometry, and in retinae from mice with heterozygous angiopoietin deficiency (Ang-2 LacZ knock-in mice). Finally, recombinant angiopoietin-2 was injected into eyes of nondiabetic rats, and pericyte numbers were quantitated in retinal capillaries. Angiopoietin-1 protein was present in the normal maturing retina and was upregulated 2.5-fold in diabetic retinae over 3 months of diabetes. In contrast, angiopoietin-2 protein was consistently upregulated more than 30-fold in the retinae of diabetic rats, preceding the onset of pericyte loss. Heterozygous angiopoietin-2 deficiency completely prevented diabetes-induced pericyte loss and reduced the number of acellular capillary segments. Injection of angiopoietin-2 into the eyes of normal rats induced a dose-dependent pericyte loss. These data show that upregulation of angiopoietin-2 plays a critical role in the loss of pericytes in the diabetic retina.


Pharmacological Targets and the Biological Mechanisms of Formononetin for Alzheimer's Disease: A Network Analysis.
BACKGROUND This study aimed to identify the pharmacological targets and mechanisms of action of the traditional Chinese medicine, formononetin, in the treatment of Alzheimer's disease (AD) using network pharmacological analysis. MATERIAL AND METHODS Targets of AD were obtained by using DisGeNET gene discovery platform, the herbal ingredients target (HIT) database, the SuperPred, and the SwissTargetPrediction compound target prediction platforms. Pathogenic and therapeutic targets were imported to the STRING biological database, and Cytoscape network integration software was used to construct component-target and disease-target interaction networks. Core targets were identified by topological analysis and were further tested to identify the biological processes and signaling pathways. RESULTS Seven key target genes for formononetin in the treatment of patients with AD were identified, including estrogen receptor alpha (ESR1), peroxisome proliferator-activated receptor gamma (PPARG), tumor protein p53 (TP53), sirtuin 1 (SIRT1), tumor necrosis factor (TNF), cytochrome P450 19A1 (CYP19A1), and nuclear factor (erythroid-derived 2)-like 2 (NFE2L2). The biological processes included hormone metabolism, regulation of nucleoside, nucleotide and nucleic acid metabolism, apoptosis, energy pathways, metabolism, cell communication, and signal transduction. The signaling pathways included histone acetylation and deacetylation (HDAC) class I, regulation of p38-alpha/beta, p38 mitogen-activated protein kinase (MAPK) signaling pathway, bone morphogenetic protein (BMP) receptor signaling, interleukin-1 (IL1) mediated signaling events, the tumor necrosis factor (TNF) receptor signaling pathway, and cytoplasmic and nuclear Smad2/3 signaling. CONCLUSIONS Pharmacological network analysis was used to identify the gene targets and mechanisms of formononetin treatment in patients with AD.


Amplification of the gli gene in childhood sarcomas.
The gli gene, originally identified by its amplified copy number in cells from a human malignant glioma, has a predicted translation product that contains five tandem DNA-binding zinc finger motifs related to those of Krüppel, a developmentally important Drosophila segmentation gene. Because of the potential importance of overproduction of this protein in neoplastic development, we examined DNAs from 29 cases of childhood sarcoma for evidence of amplification of the gli gene. In one of the 13 rhabdomyosarcomas studied, genomic DNA restriction fragments containing the gli gene were amplified approximately 30-fold, and expression of the 4.0-kilobase gli mRNA transcript was identified. The tumor with gli gene amplification lacked the usual histological features of alveolar or embryonal rhabdomyosarcoma; however, ultrastructural analysis of tumor cells established in culture revealed attenuated sarcomeres, resembling those found in primitive rhabdomyoblasts. Cytogenetic analysis of this cell line disclosed double-minute chromatin bodies, with no apparent rearrangements in the region of the gli locus on the long arm of chromosome 12, bands q13 to q14.3. A 15-fold level of gli amplification and gli mRNA transcripts were also detected in an established cell line from a patient with a rare form of osteosarcoma characterized by multipotential histological features. A similar level of gli gene amplification was observed in cryopreserved primary tumor cells from this patient, confirming that gene amplification took place during tumor development and not during in vitro cell culture. Amplified gli sequences were cytogenetically localized by in situ hybridization to a homogeneously staining region contained on a derivative chromosome 7. Of eight osteosarcomas and seven Ewing's sarcomas with typical histopathological features, none had detectable rearrangements or amplification of gli sequences. Thus, gli gene amplification in childhood sarcomas appears restricted to tumors with primitive histopathological features, perhaps reflecting overproduction of a gene product able to influence gene expression during early mesenchymal cell development.


Expression of angiopoietin-2 in human glioma cells and its role for angiogenesis.
In highly vascular malignant glioma, glioma cells themselves may express angiogenic factors and induce angiogenesis. Recent studies have shown that novel angiogenic factors, angiopoietin-1 (Ang1) and -2 (Ang2), play important roles in the modulation of vasculogenesis and angiogenesis. In this study, we determined Ang2 mRNA expression in cultured human malignant glioma cells (U105, U251, and U373 MG) by reverse transcriptase-PCR. Western blot analysis and immunocytochemical analysis with antihuman Ang2 antibody revealed that Ang2 protein was expressed and secreted by these cells. Furthermore, hypoxia increased the Ang2 protein level in cultured glioma cells. Serial sections of 32 human glioma tissues (14 glioblastomas, eight anaplastic astrocytomas, seven astrocytomas, and three pilocytic astrocytomas) were immunostained against Ang2, vascular endothelial growth factor, Tie2, von Willebrand factor, and alpha smooth muscle actin. The immunoreactivity of each angiogenic factor was higher in malignant gliomas than in low-grade gliomas. Ang2 protein was detected not only in endothelial cells but also in glioma cells, and its expression was prominent in both the area surrounding the necrosis and the periphery of glioblastomas. In the area surrounding necrosis, Ang2 was highly expressed and tumor vessels showed regression. In the tumor periphery, Ang2 was highly expressed and many small vessels stained positively for von Willebrand factor but not for alpha smooth muscle actin, suggesting angiogenesis. Statistical analysis revealed that the Ang2 expression was negatively correlated with vessel maturation in malignant gliomas and that vascular endothelial growth factor expression was positively correlated with vessel maturation in low-grade gliomas (P < 0.05). These results suggest that glioma cells themselves express Ang2 and that expression may be induced by hypoxic stimulation and may play a crucial role in the vessel maturation, angiogenesis, and vessel regression in malignant glioma.


Bayesian analysis of gene expression levels: statistical quantification of relative mRNA level across multiple strains or treatments.
Methods of microarray analysis that suit experimentalists using the technology are vital. Many methodologies discard the quantitative results inherent in cDNA microarray comparisons or cannot be flexibly applied to multifactorial experimental design. Here we present a flexible, quantitative Bayesian framework. This framework can be used to analyze normalized microarray data acquired by any replicated experimental design in which any number of treatments, genotypes, or developmental states are studied using a continuous chain of comparisons. We apply this method to Saccharomyces cerevisiae microarray datasets on the transcriptional response to ethanol shock, to SNF2 and SWI1 deletion in rich and minimal media, and to wild-type and zap1 expression in media with high, medium, and low levels of zinc. The method is highly robust to missing data, and yields estimates of the magnitude of expression differences and experimental error variances on a per-gene basis. It reveals genes of interest that are differentially expressed at below the twofold level, genes with high 'fold-change' that are not statistically significantly different, and genes differentially regulated in quantitatively unanticipated ways. Anyone with replicated normalized cDNA microarray ratio datasets can use the freely available MacOS and Windows software, which yields increased biological insight by taking advantage of replication to discern important changes in expression level both above and below a twofold threshold. Not only does the method have utility at the moment, but also, within the Bayesian framework, there will be considerable opportunity for future development.


Self-help groups as mutual support: what do carers value?
The literature suggests that the United Kingdom, in common with Europe, North America, Canada and Scandinavia, has seen significant growth in single-issue self-help/mutual aid groups concerned with health and social care issues since the 1970s, but there is only ad hoc academic and policy interest in such groups in the United Kingdom. This article presents findings from a doctoral study with two self-help/mutual aid groups for carers in South-East England. The data are drawn from semistructured interviews with 15 active members which explored reasons for joining, benefits derived from membership, and perceived differences between support gained by membership and their relationship with professionals. Most group members had prior experience of voluntary work/activity, which influenced their decision to join, often prompted by a failure of the 'usual' support network of family/friends to cope or adjust to the carer's needs. Members reported personal gains of empathy, emotional information, experiential knowledge and practical information, based on a core value of reciprocity through peer support. It is this latter benefit that sets apart membership of self-help groups from groups supported by professionals who may not appreciate the scope and breadth of carers' responsibilities, or of the importance of their relationship with the person for whom they care. In this way, self-help groups offered additional, but not alternative, 'space' that enabled members to transcend their traditional role as a 'carer'. It is concluded that self-help/mutual aid groups, based on reciprocal peer support, offer a valuable type of resource in the community that is not replicable in professional-client relations. The findings have contemporary relevance given the raft of new policies which value the experiential knowledge built by both individual and collectives of carers.


Imaging Foveal Microvasculature: Optical Coherence Tomography Angiography Versus Adaptive Optics Scanning Light Ophthalmoscope Fluorescein Angiography.
To compare the use of optical coherence tomography angiography (OCTA) and adaptive optics scanning light ophthalmoscope fluorescein angiography (AOSLO FA) for characterizing the foveal microvasculature in healthy and vasculopathic eyes. Four healthy controls and 11 vasculopathic patients (4 diabetic retinopathy, 4 retinal vein occlusion, and 3 sickle cell retinopathy) were imaged with OCTA and AOSLO FA. Foveal perfusion maps were semiautomatically skeletonized for quantitative analysis, which included foveal avascular zone (FAZ) metrics (area, perimeter, acircularity index) and vessel density in three concentric annular regions of interest. On each set of OCTA and AOSLO FA images, matching vessel segments were used for lumen diameter measurement. Qualitative image comparisons were performed by visual identification of microaneurysms, vessel loops, leakage, and vessel segments. Adaptive optics scanning light ophthalmoscope FA and OCTA showed no statistically significant differences in FAZ perimeter, acircularity index, and vessel densities. Foveal avascular zone area, however, showed a small but statistically significant difference of 1.8% (P = 0.004). Lumen diameter was significantly larger on OCTA (mean difference 5.7 μm, P < 0.001). Microaneurysms, fine structure of vessel loops, leakage, and some vessel segments were visible on AOSLO FA but not OCTA, while blood vessels obscured by leakage were visible only on OCTA. Optical coherence tomography angiography is comparable to AOSLO FA at imaging the foveal microvasculature except for differences in FAZ area, lumen diameter, and some qualitative features. These results, together with its ease of use, short acquisition time, and avoidance of potentially phototoxic blue light, support OCTA as a tool for monitoring ocular pathology and detecting early disease.


Investigating Biological Assumptions through Radical Reimplementation.
An important goal in both artificial life and biology is uncovering the most general principles underlying life, which might catalyze both our understanding of life and engineering lifelike machines. While many such general principles have been hypothesized, conclusively testing them is difficult because life on Earth provides only a singular example from which to infer. To circumvent this limitation, this article formalizes an approach called radical reimplementation. The idea is to investigate an abstract biological hypothesis by intentionally reimplementing its main principles to diverge maximally from existing natural examples. If the reimplementation successfully exhibits properties resembling biology, it may support the underlying hypothesis better than an alternative example inspired more directly by nature. The approach thereby provides a principled alternative to a common tradition of defending and minimizing deviations from nature in artificial life. This work reviews examples that can be interpreted through the lens of radical reimplementation to yield potential insights into biology despite having purposely unnatural experimental setups. In this way, radical reimplementation can help renew the relevance of computational systems for investigating biological theory and can act as a practical philosophical tool to help separate the fundamental features of terrestrial biology from the epiphenomenal.


Clinical significance of venom antigen levels in patients envenomed by the Malayan pit viper (Calloselasma rhodostoma).
Serial venom antigen levels were measured by enzyme-linked immunosorbent assay (ELISA) in 46 patients with systemic envenoming by the Malayan pit viper (Calloselasma rhodostoma), a major cause of snake bite in Southeast Asia. The principal effects of the venom are defibrination, hemorrhage and local tissue necrosis. Admission venom levels, which varied between 0 and 595 ng/ml, correlated with the incidence of spontaneous systemic bleeding, blood incoagulability and concentrations of plasma fibrinogen and serum fibrin degradation products. The presence or absence of nonclotting blood also correlated with the time elapsed between the bite and hospital admission. The development of nonclotting blood may be delayed by up to 72 hr after the bite even though circulating venom and raised FDP may be detected at presentation. This is probably explained by a temporary equilibrium between synthesis and consumption of fibrinogen. Venom antigenemia recurred in 12 patients (26%) suggesting continuous absorption of venom from the wound or saturation of extravascular binding sites. Admission venom levels also correlated with the extent of local swelling and the occurrence of tissue necrosis at the site of the bite. Venom was detected in 87% of wound aspirates and 88% of urine specimens taken on admission. Tourniquets, of the type used in rural Thailand, did not delay the absorption of venom into the circulation.


Intramyocardial, autologous CD34+ cell therapy for refractory angina.
A growing number of patients with coronary disease have refractory angina. Preclinical and early-phase clinical data suggest that intramyocardial injection of autologous CD34+ cells can improve myocardial perfusion and function. Evaluate the safety and bioactivity of intramyocardial injections of autologous CD34+ cells in patients with refractory angina who have exhausted all other treatment options. In this prospective, double-blind, randomized, phase II study (ClinicalTrials.gov identifier: NCT00300053), 167 patients with refractory angina received 1 of 2 doses (1×10(5) or 5×10(5) cells/kg) of mobilized autologous CD34+ cells or an equal volume of diluent (placebo). Treatment was distributed into 10 sites of ischemic, viable myocardium with a NOGA mapping injection catheter. The primary outcome measure was weekly angina frequency 6 months after treatment. Weekly angina frequency was significantly lower in the low-dose group than in placebo-treated patients at both 6 months (6.8±1.1 versus 10.9±1.2, P=0.020) and 12 months (6.3±1.2 versus 11.0±1.2, P=0.035); measurements in the high-dose group were also lower, but not significantly. Similarly, improvement in exercise tolerance was significantly greater in low-dose patients than in placebo-treated patients (6 months: 139±151 versus 69±122 seconds, P=0.014; 12 months: 140±171 versus 58±146 seconds, P=0.017) and greater, but not significantly, in the high-dose group. During cell mobilization and collection, 4.6% of patients had cardiac enzyme elevations consistent with non-ST segment elevation myocardial infarction. Mortality at 12 months was 5.4% in the placebo-treatment group with no deaths among cell-treated patients. Patients with refractory angina who received intramyocardial injections of autologous CD34+ cells (10(5) cells/kg) experienced significant improvements in angina frequency and exercise tolerance. The cell-mobilization and -collection procedures were associated with cardiac enzyme elevations, which will be addressed in future studies.


Fungal infections in liver transplant recipients.
Sixty-two adults who underwent orthotopic liver transplantations between February 1981 and June 1983 were followed for a mean of 170 days after the operation. Twenty-six patients developed 30 episodes of significant fungal infection. Candida species and Torulopsis glabrata were responsible for 22 episodes and Aspergillus species for 6. Most fungal infections occurred in the first month after transplantation. In the first 8 weeks after transplantation, death occurred in 69% (18/26) of patients with fungal infection but in only 8% (3/36) of patients without fungal infection (P less than 0.0005). The cause of death, however, was usually multifactorial, and not solely due to the fungal infection. Fungal infections were associated with the following clinical factors: administration of preoperative steroids (P less than 0.05) and antibiotics (P less than 0.05), longer transplant operative time (P less than 0.02), longer posttransplant operative time (P less than 0.01), duration of antibiotic use after transplant surgery (P less than 0.001), and the number of steroid boluses administered to control rejection in the first 2 posttransplant months (P less than 0.01). Patients with primary biliary cirrhosis had fewer fungal infections than patients with other underlying liver diseases (P less than 0.05). A total of 41% (9/22) of Candida infections resolved, but all Aspergillus infections ended in death.


Trust and the development of health care as a social institution.
Health systems are inherently relational and so many of the most critical challenges for health systems are relationship and behaviour problems. Yet the disciplinary perspectives that underlie traditional health policy analysis offer only limited and partial insights into human behaviour and relationships. The health sector, therefore, has much to learn from the wider literature on behaviour and the factors that influence it. A central feature of recent debates, particularly, but not only, in relation to social capital, is trust and its role in facilitating collective action, that is co-operation among people to achieve common goals. The particular significance of trust is that it offers an alternative approach to the economic individualism that has driven public policy analysis in recent decades. This paper considers what the debates on trust have to offer health policy analysis by exploring the meaning, bases and outcomes of trust, and its relevance to health systems. It, first, presents a synthesis of theoretical perspectives on the notion of trust. Second, it argues both that trust underpins the co-operation within health systems that is necessary to health production, and that a trust-based health system can make an important contribution to building value in society. Finally, five conclusions are drawn for an approach to health policy analysis that takes trust seriously.


Alcohol Consumption Modulates Host Defense in Rhesus Macaques by Altering Gene Expression in Circulating Leukocytes.
Several lines of evidence indicate that chronic alcohol use disorder leads to increased susceptibility to several viral and bacterial infections, whereas moderate alcohol consumption decreases the incidence of colds and improves immune responses to some pathogens. In line with these observations, we recently showed that heavy ethanol intake (average blood ethanol concentrations > 80 mg/dl) suppressed, whereas moderate alcohol consumption (blood ethanol concentrations < 50 mg/dl) enhanced, T and B cell responses to modified vaccinia Ankara vaccination in a nonhuman primate model of voluntary ethanol consumption. To uncover the molecular basis for impaired immunity with heavy alcohol consumption and enhanced immune response with moderate alcohol consumption, we performed a transcriptome analysis using PBMCs isolated on day 7 post-modified vaccinia Ankara vaccination, the earliest time point at which we detected differences in T cell and Ab responses. Overall, chronic heavy alcohol consumption reduced the expression of immune genes involved in response to infection and wound healing and increased the expression of genes associated with the development of lung inflammatory disease and cancer. In contrast, chronic moderate alcohol consumption upregulated the expression of genes involved in immune response and reduced the expression of genes involved in cancer. To uncover mechanisms underlying the alterations in PBMC transcriptomes, we profiled the expression of microRNAs within the same samples. Chronic heavy ethanol consumption altered the levels of several microRNAs involved in cancer and immunity and known to regulate the expression of mRNAs differentially expressed in our data set.


On the role of length of stay in healthcare-associated bloodstream infection.
We conducted a retrospective cohort study to examine the role played by length of hospital stay in the risk of healthcare-associated bloodstream infection (BSI), independent of demographic and clinical risk factors for BSI. We employed data from 113,893 admissions from inpatients discharged between 2006 and 2008. Large tertiary healthcare center in New York City. We estimated the crude and adjusted hazard of BSI by conducting logistic regression using a person-day data structure. The covariates included in the fully adjusted model included age, sex, Charlson score of comorbidity, renal failure, and malignancy as static variables and central venous catheterization, mechanical ventilation, and intensive care unit stay as time-varying variables. In the crude model, we observed a nonlinear increasing hazard of BSI with increasing hospital stay. This trend was reduced to a constant hazard when fully adjusted for demographic and clinical risk factors for BSI. The association between longer length of hospital stay and increased risk of infection can largely be explained by the increased duration of stay among those who have underlying morbidity and require invasive procedures. We should take caution in attributing the association between length of stay and BSI to a direct negative impact of the healthcare environment.


The role of baroreceptors and chemoreceptors in the regulation of the cerebral circulation.
1. Ten experiments, each using two dogs, were performed to evaluate the effect of chemoreceptor and baroreceptor activity on the cerebral circulation. 2. The carotid bifurcation areas were vascularly isolated bilaterally and perfused with arterial blood from a second animal. 3. Bilateral vagotomy interrupted stimuli from the aortic group of receptors. 4. Administration of 5% carbon dioxide to the donor animal resulted in an increase in cerebral (cortical) blood flow in the recipient. 5. A change in the arterial perfusion pressure from the donor resulted in a reciprocal change in the cerebral blood flow of the recipient. These changes were abolished by sectioning the sinus nerves.


HIV infection across aging: Synergistic effects on intrinsic functional connectivity of the brain.
The objective of the study was to examine additive and synergistic effects of age and HIV infection on resting state (RS) intra- and inter-network functional connectivity (FC) of the brain. We also aimed to assess relationships with neurocognition and determine clinical-, treatment-, and health-related factors moderating intrinsic brain activity in aging HIV-positive (HIV+) individuals. The current report presents data on 54 HIV+ individuals (age M = 41, SD = 12 years) stabilized on cART and 54 socio-demographically matched healthy (HIV-) comparators (age M = 43, SD = 12 years), with cohort education mean of 16 years (SD = 12). Age at seroconversion ranged 20-55 years old. ANOVA assessed additive and synergistic effects of age and HIV in 133 ROIs. Bivariate statistics examined relationships of FC indices vulnerable to age-HIV interactions and neurocognitive domains T-scores (attention, executive, memory, psychomotor, semantic skills). Multivariate logistic models determined covariates of FC. This study found no statistically significant age-HIV effects on RS-FC after correcting for multiple comparisons except for synergistic effects on connectivity within cingulo-opercular network (CON) at the trending level. However, for uncorrected RS connectivity analyses, we observed HIV-related strengthening between regions of fronto-parietal network (FPN) and default mode network (DMN), and particular DMN regions and sensorimotor network (SMN). Simultaneously, FC weakening was observed within FPN and between other regions of DMN-SMN, in HIV+ vs. HIV- individuals. Ten ROI pairs revealed age-HIV interactions, with FC decreasing with age in HIV+, while increasing in controls. FC correlated with particular cognitive domains positively in HIV+ vs. negatively in HIV- group. Proportion of life prior-to-after HIV-seroconversion, post-infection years, and treatment determined within-FPN and SMN-DMN FC. In sum, highly functioning HIV+/cART+ patients do not reveal significantly altered RS-FC from healthy comparators. Nonetheless, the current findings uncorrected for multiple comparisons suggest that HIV infection may lead to simultaneous increases and decreases in FC in distinct brain regions even in patients successfully stabilized on cART. Moreover, RS-fMRI ROI-based analysis can be sensitive to age-HIV interactions, which are especially pronounced for inter-network FC in relation to neurocognition. Aging and treatment-related factors partially explain RS-FC in aging HIV+ patients.


Probabilistic reasoning and clinical decision-making: do doctors overestimate diagnostic probabilities?
The "threshold approach" is based on a physician's assessment of the likelihood of a disease expressed as a probability. The use of Bayes' theorem to calculate disease probability in patients with and without a particular characteristic, may be hampered by the presence of subadditivity (i.e. the sum of probabilities concerning a single case scenario exceeding 100%). To assess the presence of subadditivity in physicians' estimations of probabilities and the degree of concordance among doctors in their probability assessments. Prospective questionnaire. Residents and trained physicians in Family Medicine, Internal Medicine and Cardiology (n = 84) were asked to estimate the probability of each component of the differential diagnosis in a case scenario describing a patient with chest pain. Subadditivity was exhibited in 65% of the participants. The total sum of probabilities given by each participant ranged from 44% to 290% (mean 137%). There was wide variability in the assignment of probabilities for each diagnostic possibility (SD 16-21%). The finding of substantial subadditivity, coupled with the marked discordance in probability estimates, questions the applicability of the threshold approach. Physicians need guidance, explicit tools and formal training in probability estimation to optimize the use of this approach in clinical practice.


Fra-1 expression in malignant and benign thyroid tumor.
The differential diagnosis of thyroid nodules is very important in deciding the treatment modality and the fine needle aspiration is the best diagnostic method. But, there are some limitations in use because of inadequate test materials and difficulty in interpreting. According to the study of oncogene and tumor suppressor gene about the origin of thyroid tumor, expression of Fra-1, one of AP-1 complex, is increased in thyroid neoplasm, though not present in the normal tissue. So, there is a possibility that it will be used as a method for the differential diagnosis of thyroid nodules. We tried to know whether presence or absence of Fra-1 expression can be used as a diagnostic method in differential diagnosis of thyroid nodules using the immunohistochemical (IHC) staining method. In 4 types of thyroid tumor that were confirmed by histologic diagnosis after operation (18 cases of adenomatous goiter, 16 cases of follicular adenoma, 30 cases of papillary cancer, 10 cases of follicular cancer), IHC staining method was performed to evaluate the expression of Fra-1. In papillary and follicular thyroid cancers, the expression of Fra-1 was stronger than in benign thyroid tumor, but there was no difference in Fra-1 expression between the two types of carcinoma. Weak expression of Fra-1 was observed in all cases of follicular adenoma, though it was weaker than in carcinoma, and it was also weakly expressed only in some cases (33%) of adenomatous goiter. The expression of Fra-1 was stronger in thyroid cancer than in benign thyroid tumor, but it was impossible to differentiate thyroid cancer from benign thyroid tumor by presence or absence of Fra-1 expression using IHC staining method.


Simple platform for chronic imaging of hippocampal activity during spontaneous behaviour in an awake mouse.
Chronic electrophysiological recordings of neuronal activity combined with two-photon Ca2+ imaging give access to high resolution and cellular specificity. In addition, awake drug-free experimentation is required for investigating the physiological mechanisms that operate in the brain. Here, we developed a simple head fixation platform, which allows simultaneous chronic imaging and electrophysiological recordings to be obtained from the hippocampus of awake mice. We performed quantitative analyses of spontaneous animal behaviour, the associated network states and the cellular activities in the dorsal hippocampus as well as estimated the brain stability limits to image dendritic processes and individual axonal boutons. Ca2+ imaging recordings revealed a relatively stereotyped hippocampal activity despite a high inter-animal and inter-day variability in the mouse behavior. In addition to quiet state and locomotion behavioural patterns, the platform allowed the reliable detection of walking steps and fine speed variations. The brain motion during locomotion was limited to ~1.8 μm, thus allowing for imaging of small sub-cellular structures to be performed in parallel with recordings of network and behavioural states. This simple device extends the drug-free experimentation in vivo, enabling high-stability optophysiological experiments with single-bouton resolution in the mouse awake brain.


Community health workers for ART in sub-Saharan Africa: learning from experience--capitalizing on new opportunities.
Low-income countries with high HIV/AIDS burdens in sub-Saharan Africa must deal with severe shortages of qualified human resources for health. This situation has triggered the renewed interest in community health workers, as they may play an important role in scaling-up antiretroviral treatment for HIV/AIDS by taking over a number of tasks from the professional health workers. Currently, a wide variety of community health workers are active in many antiretroviral treatment delivery sites. This article investigates whether present community health worker programmes for antiretroviral treatment are taking into account the lessons learnt from past experiences with community health worker programmes in primary health care and to what extent they are seizing the new antiretroviral treatment-specific opportunities. Based on a desk review of multi-purpose community health worker programmes for primary health care and of recent experiences with antiretroviral treatment-related community health workers, we developed an analytic framework of 10 criteria: eight conditions for successful large-scale antiretroviral treatment-related community health worker programmes and two antiretroviral treatment-specific opportunities. Our appraisal of six community health worker programmes, which we identified during field work in Ethiopia, Malawi and Uganda in 2007, shows that while some lessons from the past have been learnt, others are not being sufficiently considered and antiretroviral treatment-specific opportunities are not being sufficiently seized.In particular, all programmes have learnt the lesson that without adequate remuneration, community health workers cannot be retained in the long term. Yet we contend that the apparently insufficient attention to issues such as quality supervision and continuous training will lead to decreasing quality of the programmes over time. The life experience of people living with HIV/AIDS is still a relatively neglected asset, even though it may give antiretroviral treatment-related community health worker programmes better chances of success than their predecessors and may be crucially important for adherence and retention in large-scale antiretroviral treatment programmes. Community health workers as a community-based extension of health services are essential for antiretroviral treatment scale-up and comprehensive primary health care. The renewed attention to community health workers is thus very welcome, but the scale-up of community health worker programmes runs a high risk of neglecting the necessary quality criteria if it is not aligned with broader health systems strengthening. To achieve universal access to antiretroviral treatment, this is of paramount importance and should receive urgent attention.


Estimating population birth rates of zooplankton when rates of egg deposition and hatching are periodic.
I present a general method of computing finite birth and death rates of natural zooplankton populations from changes in the age distribution of eggs and changes in population size. The method is applicable to cases in which eggs hatch periodically owing to variable rates of oviposition. When morphological criteria are used to determine the age distribution of eggs at the beginning and end of a sampling interval, egg mortality can be incorporated in estimates of population birth rate. I raised laboratory populations of Asplanchna priodonta, a common planktonic rotifer, in semicontinuous culture to evaluate my method of computing finite birth rate. The Asplanchna population became synchronized to a daily addition of food but grew by the same amount each day once steady state was achieved. The steady-state rate of growth, which can be computed from the volume-specific dilution rate of the culture, was consistent with the finite birth rate predicted from the population's egg ratio and egg age distribution.


Scalable co-optimization of morphology and control in embodied machines.
Evolution sculpts both the body plans and nervous systems of agents together over time. By contrast, in artificial intelligence and robotics, a robot's body plan is usually designed by hand, and control policies are then optimized for that fixed design. The task of simultaneously co-optimizing the morphology and controller of an embodied robot has remained a challenge. In psychology, the theory of embodied cognition posits that behaviour arises from a close coupling between body plan and sensorimotor control, which suggests why co-optimizing these two subsystems is so difficult: most evolutionary changes to morphology tend to adversely impact sensorimotor control, leading to an overall decrease in behavioural performance. Here, we further examine this hypothesis and demonstrate a technique for 'morphological innovation protection', which temporarily reduces selection pressure on recently morphologically changed individuals, thus enabling evolution some time to 'readapt' to the new morphology with subsequent control policy mutations. We show the potential for this method to avoid local optima and converge to similar highly fit morphologies across widely varying initial conditions, while sustaining fitness improvements further into optimization. While this technique is admittedly only the first of many steps that must be taken to achieve scalable optimization of embodied machines, we hope that theoretical insight into the cause of evolutionary stagnation in current methods will help to enable the automation of robot design and behavioural training-while simultaneously providing a test bed to investigate the theory of embodied cognition.


Assessing the effects of climate on host-parasite interactions: a comparative study of European birds and their parasites.
Climate change potentially has important effects on distribution, abundance, transmission and virulence of parasites in wild populations of animals. Here we analyzed paired information on 89 parasite populations for 24 species of bird hosts some years ago and again in 2010 with an average interval of 10 years. The parasite taxa included protozoa, feather parasites, diptera, ticks, mites and fleas. We investigated whether change in abundance and prevalence of parasites was related to change in body condition, reproduction and population size of hosts. We conducted analyses based on the entire dataset, but also on a restricted dataset with intervals between study years being 5-15 years. Parasite abundance increased over time when restricting the analyses to datasets with an interval of 5-15 years, with no significant effect of changes in temperature at the time of breeding among study sites. Changes in host body condition and clutch size were related to change in temperature between first and second study year. In addition, changes in clutch size, brood size and body condition of hosts were correlated with change in abundance of parasites. Finally, changes in population size of hosts were not significantly related to changes in abundance of parasites or their prevalence. Climate change is associated with a general increase in parasite abundance. Variation in laying date depended on locality and was associated with latitude while body condition of hosts was associated with a change in temperature. Because clutch size, brood size and body condition were associated with change in parasitism, these results suggest that parasites, perhaps mediated through the indirect effects of temperature, may affect fecundity and condition of their hosts. The conclusions were particularly in accordance with predictions when the restricted dataset with intervals of 5-15 years was used, suggesting that short intervals may bias findings.


Effects of music therapy in the treatment of children with delayed speech development - results of a pilot study.
Language development is one of the most significant processes of early childhood development. Children with delayed speech development are more at risk of acquiring other cognitive, social-emotional, and school-related problems. Music therapy appears to facilitate speech development in children, even within a short period of time. The aim of this pilot study is to explore the effects of music therapy in children with delayed speech development. A total of 18 children aged 3.5 to 6 years with delayed speech development took part in this observational study in which music therapy and no treatment were compared to demonstrate effectiveness. Individual music therapy was provided on an outpatient basis. An ABAB reversal design with alternations between music therapy and no treatment with an interval of approximately eight weeks between the blocks was chosen. Before and after each study period, a speech development test, a non-verbal intelligence test for children, and music therapy assessment scales were used to evaluate the speech development of the children. Compared to the baseline, we found a positive development in the study group after receiving music therapy. Both phonological capacity and the children's understanding of speech increased under treatment, as well as their cognitive structures, action patterns, and level of intelligence. Throughout the study period, developmental age converged with their biological age. Ratings according to the Nordoff-Robbins scales showed clinically significant changes in the children, namely in the areas of client-therapist relationship and communication. This study suggests that music therapy may have a measurable effect on the speech development of children through the treatment's interactions with fundamental aspects of speech development, including the ability to form and maintain relationships and prosodic abilities. Thus, music therapy may provide a basic and supportive therapy for children with delayed speech development. Further studies should be conducted to investigate the mechanisms of these interactions in greater depth. The trial is registered in the German clinical trials register; Trial-No.: DRKS00000343.


Global health trials methodological research agenda: results from a priority setting exercise.
Methodological research into the design, conduct, analysis and reporting of trials is essential to optimise the process. UK specialists in the field have established a set of top priorities in aid of this research. These priorities, however, may not be reflected in the needs of similar research in low- to middle-income countries (LMICs) with different healthcare provision, resources and research infrastructure. The aim of the study was to identify the top priorities for methodological research in LMICs to inform further research and ultimately to improve clinical trials in these regions. An online, two-round survey was conducted from December 2016 to April 2017 amongst researchers and methodologists working on trials in LMICs. The first round required participants to suggest between three and six topics which they felt were priorities for trial methodological research in LMICs. The second round invited participants to grade the importance of a compulsory list of topics suggested by four or more individuals, and an optional list of the remaining topics. Rounds 1 and 2 were completed by 412 and 314 participants, respectively. A wide spread of years of experience, discipline, current country of residence, origin of trials training and area of involvement in trials was reported. The topics deemed most important for methodological research were: choosing appropriate outcomes to measure and training of research staff. By presenting these top priorities we have the foundations of a global health trials methodological research agenda which we hope will foster future research in specific areas in order to increase and improve trials in LMICs.


Unique [(1)infinityNi(8)Bi(8)S] metallic wires in a novel quasi-1D compound. Synthesis, crystal and electronic structure, and properties of Ni(8)Bi(8)SI.
A new quasi-one-dimensional compound Ni(8)Bi(8)SI has been synthesized and its crystal structure determined from single-crystal X-ray diffraction data. The structure of Ni(8)Bi(8)SI consists of [(1)infinityNi(8)Bi(8)S] columns separated by iodine atoms. Conductivity and magnetic susceptibility measurements (down to 4.2 K) show that Ni(8)Bi(8)SI is a one-dimensional metal and exhibits Pauli paramagnetic properties. These observations are in good agreement with the results from electronic structure calculations. An analysis of the chemical bonding employing difference electron charge density maps reveals strong multicenter Ni-Bi bonds and pair Ni-S interactions within the [(1)infinityNi(8)Bi(8)S] columns. Only electrostatic interactions are inferred between the columns and iodine atoms.


How to introduce virtual microscopy (VM) in routine diagnostic pathology: constraints, ideas, and solutions.
Virtual microscopy which is the diagnostic work with digitized microscopic images in tissue - based diagnosis is in its childhood in being implemented in routine diagnosis. Until today, only a few pathology institutions take use of this new technology, although it is available since several years. Why? Virtual microscopy requires a new workflow organisation in the pathologist's diagnostic procedure. At a first view, the laboratory workflow seems to remain untouched to a high degree. However, the used laboratory information system (LIS), which is commonly built in a hierarchic order, has to be adjusted at its highest levels, i.e., diagnosis statement, quality evaluation, submission to the clinician (hospital information system), and feedback to the laboratory. Therefore, the laboratory's workflow is involved at all levels too, and the LIS has to be changed or adjusted to the requirements of VM. VM systems are usually equipped with a viewer that mimics the viewing of a conventional microscope, and do not offer access to sensitive nodes of the LIS. Similar, LIS are usually closed and fixed systems because of data security and certification demands. Thus, VM systems have to possess communication access at different LIS levels together with steering commands for the LIS in close association with the diagnostic quality and efficiency (for example demands for additional stains, immunohistochemical or quantitative image methods, etc.), as well as expert consultation, or panel discussion. An implementation of an open and active LIS - VM management system could significantly promote the introduction of VM into routine diagnostic surgical pathology. The management system has to coordinate and translate the demands of VM to LIS (and vice versa), and to assure the communication with HIS. Mandatory features include streaming of the laboratory workflow, feedback commands to LIS, as well as regulation of temporary priority levels. A successful implementation of VM systems in routine tissue-based diagnosis requires communicative management systems as long as VM is considered to be a "stand alone system" that just mimics a conventional microscope.


The built environment and active transportation safety in children and youth: a study protocol.
Active transportation, such as walking and biking, is a healthy way for children to explore their environment and develop independence. However, children can be injured while walking and biking. Many cities make changes to the built environment (e.g., traffic calming features, separated bike lanes) to keep people safe. There is some research on how effective these changes are in preventing adult pedestrians and bicyclists from getting hurt, but very little research has been done to show how safe various environments are for children and youth. Our research program will study how features of the built environment affect whether children travel (e.g., to school) using active modes, and whether certain features increase or decrease their likelihood of injury. First, we will use a cross-sectional study design to estimate associations between objectively measured built environment and objectively measured active transportation to school among child elementary students. We will examine the associations between objectively measured built environment and child and youth pedestrian-motor vehicle collisions (MVCs) and bicyclist-MVCs. We will also use these data to determine the space-time distribution of pedestrian-MVCs and bicyclist-MVCs. Second, we will use a case-crossover design to compare the built environment characteristics of the site where child and youth bicyclists sustain emergency department reported injuries and two randomly selected sites (control sites) along the bicyclist's route before the injury occurred. Third, to identify implementation strategies for built environment change at the municipal level to encourage active transportation we will conduct: 1) an environmental scan, 2) key informant interviews, 3) focus groups, and 4) a national survey to identify facilitators and barriers for implementing built environment change in municipalities. Finally, we will develop a built environment implementation toolkit to promote active transportation and prevent child pedestrian and bicyclist injuries. This program of research will identify the built environment associated with active transportation safety and form an evidence base from which municipalities can draw information to support change. Our team's national scope will be invaluable in providing information regarding the variability in built environment characteristics and is vital to producing evidence-based recommendations that will increase safe active transportation.


Effect of bone-marrow-derived mesenchymal stem cells on high-potential hepatocellular carcinoma in mouse models: an intervention study.
There are two completely contradictory views regarding the impact of human bone-marrow-derived mesenchymal stem cells (hMSCs) on hepatocellular carcinomas (HCCs). The aim of this study was to investigate the effect of hMSC engraftment on HCC tissues in nude mouse models, and assess the effect on metastatic potential of HCC. hMSCs were engrafted into the nude mouse models of high metastatic HCC via the tail vein. The mice in the experimental group were engrafted with hMSCs (5 × 105 cells per mouse) via the tail vein 15 days after inoculation of tumor cells, twice a week, while the animals in the control group were injected with hMSC culture medium (0.2 mL per mouse) via the tail vein. The subcutaneous tumor size was measured using an electronic digital caliper once every 4 days after hMSC engraftment. After 2, 3, 4, 5 and 6 weeks of tumor cell inoculation, the mice were killed and the tumors were collected in their entirety. The tumor weights and body weights of mice were measured, and the tumor inhibition rate was calculated. Quantitative real-time polymerase chain reaction (RT-PCR) was used to determine the expression of metastasis-related genes including osteopontin (OPN), bone sialoprotein (BSP) and integrin α5 subunit (α-V) in the mouse models of high-metastatic HCC, and the expression of apoptosis-related genes including B cell lymphoma/leukemia-2 (Bcl2), Bcl-2 associated X protein (Bax) and caspase 3 in tumor samples. The tumor weight inhibition rate was 26.62% at 2 weeks, 52.00% at 3 weeks, 38.20% at 4 weeks, 31.98% at 5 weeks, and 30.23% at 6 weeks. Tumor tissue weight comparison results were significantly lower in the hMSC engraftment groups than in the control group at the second and third weeks. The expression of metastasis-related factors OPN, BSP and α-V gene was downregulated with time. The expression of antiapoptotic gene Bcl2 exhibited an obvious declining tendency, while the expression of apoptotic genes Bax and caspase 3 showed an obvious rising tendency. The expression of α-V and BSP significantly correlated positively with the expression of Bcl2, and negatively correlated with the expression of Bax and caspase 3. The tumor inhibition rate was not significantly correlated with the expression of antiapoptotic and apoptotic factors, and α-V and BSP factors, though it exhibited a significantly negative correlation with the expression of OPN. The highest tumor inhibition rate was observed 3 weeks after hMSCs engraftment, and the tumor inhibition rate gradually reduced with the progression of time. The metastatic potential of tumor cells was downregulated after hMSC engraftment and hMSCs induce further tumor cells apoptosis. The decrease in the proliferation ability of tumor cells may induce a decline in metastatic potential in tumor cells.


War related sexual violence and it's medical and psychological consequences as seen in Kitgum, Northern Uganda: A cross-sectional study.
Despite the recent adoption of the UN resolution 1820 (2008) which calls for the cessation of war related sexual violence against civilians in conflict zones, Africa continues to see some of the worst cases of war related sexual violence including the mass sexual abuse of entire rural communities particularly in the Great Lakes region. In addition to calling for a complete halt to this abuse, there is a need for the systematic study of the reproductive, surgical and psychological effects of war related sexual violence in the African socio-cultural setting.This paper examines the specific long term health consequences of war related sexual violence among rural women living in two internally displaced person's camps in Kitgum district in war affected Northern Uganda who accessed the services of an Isis-Women's International Cross Cultural Exchange (Isis-WICCE) medical intervention. The study employed a purposive cross-sectional study design where 813 respondents were subjected to a structured interview as part of a screening procedure for an emergency medical intervention to identify respondents who required psychological, gynaecological and surgical treatment. Over a quarter (28.6%) of the women (n = 573) reported having suffered at least one form of war related sexual violence. About three quarters of the respondents had 'at least one gynaecological complaint' (72.4%) and 'at least one surgical complaint' (75.6%), while 69.4% had significant psychological distress scores (scores greater than or equal to 6 on the WHO SRQ-20). The factors that were significantly associated with war related sexual violence were the age group of less than or equal to 44 years, being Catholic, having suffered other war related physical trauma, and having 'at least one gynaecological complaint'. The specific gynaecological complaints significantly associated with war related sexual violence were infertility, chronic lower abdominal pain, abnormal vaginal bleeding, and sexual dysfunction. In a multivariable analysis the age group of less than or equal to 44 years, being Catholic and having 'at least one gynaecological complaint' remained significantly associated with war related sexual violence. The results from this study demonstrate that war related sexual violence is independently associated with the later development of specific gynaecological complaints.


Performance and environmental impact of biodegradable polymers as agricultural mulching films.
In the aim of resolving environmental key issues such as irreversible soil pollution by non-biodegradable and non-recoverable polyethylene (PE) fragments, a full-scale field experiment was set up to evaluate the suitability of four biodegradable materials based on poly(butylene adipate-co-terephtalate) (PBAT) to be used as sustainable alternatives to PE for mulching application in vineyard. Initial ultimate tensile properties, functional properties during field ageing (water vapour permeability and radiometric properties), biodegradability and agronomical performance of the mulched vines (wood production and fruiting yield) were studied. In spite of their early loss of physical integrity that occurred only five months after vine planting, the four materials satisfied all the requested functional properties and led to agronomic performance as high as polyethylene. In the light of the obtained results, the mulching material lifespan was questioned in the case of long-term perennial crop such as grapevine. Taking into account their mulching efficiency and biodegradability, the four PBAT-based studied materials are proven to constitute suitable alternatives to the excessively resistant PE material.


Risk-assessment models for predicting venous thromboembolism among hospitalized non-surgical patients: a systematic review.
Venous thromboembolism (VTE) prophylaxis is suboptimal in American hospitals despite long-standing evidence-based recommendations. Data from observational studies indicate a lower uptake of effective prophylaxis in patients hospitalized with medical versus surgical conditions. Reluctance to use prophylaxis in medical patients has been attributed to difficulty in identifying at-risk patients and balancing risks of bleeding against occurrence of VTE. Several risk-assessment models (RAMs) have been proposed to assist physicians in identifying non-surgical patients who need prophylaxis. We conducted a systematic review of published RAMs, based on objective criteria, to determine whether any RAM is validated sufficiently to be employed in clinical practice. We identified 11 RAMs, six derived from primary data and five based on expert opinion. The number, types, and strength of association of VTE risk predictors were highly variable. The variability in methods and outcome measurement precluded pooled estimates of these different models. Published RAMs for VTE lack generalizability and adequate validation. As electronic health records become more ubiquitous, validated dynamic RAMs are needed to assess VTE risk at the point-of-care in real time.


Honey, pollen, and propolis extracts show potent inhibitory activity against the zinc metalloenzyme carbonic anhydrase.
Three different honey extracts from the endemic plant in the Black Sea region Rhododendron ponticum, were investigated for their inhibitory effects against the metalloenzyme carbonic anhydrase (CA, EC 22.214.171.124), more precisely the human (h) isoforms hCA I and hCA II. Hexane, methanol, ethanol, and water solid-phase extractions (SPEs) showed inhibitory activity towards the two CA isozymes which were related to the total phenolic content. The highest inhibitory effects (0.036-0.039 mg/mL) were those of propolis methanolic extract. Among the three different samples investigated here, the aqueous extracts showed lower inhibitory effects compared to the organic solvent SPE extracts (in the range of 1.150- 5.144 mg/mL). The studied honey extracts constitute an interesting source of phenolic derivatives that might serve to identify lead compounds, targeting the physiologically relevant enzymes CA I and CA II.


Infection rates in intensive care units by electrocardiographic lead wire type: disposable vs reusable.
It is unknown if disposable electrocardiographic lead wires (ECG-LWs) reduce infection rates compared with cleaned, reusable lead wires. To compare infection rates in intensive care unit (ICU) patients receiving disposable versus reusable ECG-LWs. Matched adult ICUs were randomly assigned to disposable or reusable ECG-LWs. Outcomes were bloodstream infection, ventilator-associated pneumonia, and chest surgical site infections. Patients' characteristics and infections were collected from hospital databases. Event rates were described by using total counts and rates per 100 patient days and were compared between groups by using generalized linear mixed-effect models weighted by patients' ICU length of stay. Overall, 4056 patients from 6 ICUs received disposable and 3184 patients from 5 ICUs received reusable ECG-LWs. The characteristics of the 2 groups were similar, except patients receiving disposable ECG-LWs were less likely to be discharged home (P = .03) and had more comorbid conditions (P = .002). Overall infection rates did not differ between ECG-LW groups, between groups in matched ICUs, between groups by infection type, or when only patients with ICU stays longer than 48 hours were considered (2578 cases). In multivariate analyses, infection rates did not differ between all patients in ECG-LW groups or for patients with ICU stays beyond 48 hours (both P = .10). No difference was observed in infection rates of ICU patients receiving disposable versus reusable ECG-LWs.


Qualitative study exploring the well-being experiences of paediatric critical care consultants working in the UK during the COVID-19 pandemic.
The aim of this study was to examine the well-being experiences of consultants working in paediatric critical care (PCC) settings in the UK during the COVID-19 pandemic. Qualitative design using individual interviews and thematic analysis. PCC. Eleven medical consultants working in PCC in a range of PCC settings/transport teams in the UK from nine units participated. Participants ranged in years of experience as a consultant from four to 23 years. A set of open semistructured questions were used to elicit information about participants' experiences of workplace well-being. Interviews were audiorecorded and transcribed. Thematic analysis identified six themes and data saturation was reached. These were as follows: (1) positive and negative impact of working during COVID-19, (2) job satisfaction and public scrutiny in the unique environment of PCC, (3) supporting the workforce through modified shift work, (4) perceptions of support and recognition offered from the hospital management, (5) successful coping strategies are personal and adaptive, and (6) importance of civility and good teamwork CONCLUSION: Findings show that consultants' well-being is challenged in a number of ways and that the solutions to the problem of burn-out are multifaceted. Action is required from individual consultants, clinical teams, hospital management and national regulatory bodies. Our work corroborates the recent General Medical Council report highlighting doctors' core needs for well-being: autonomy, belonging, competence. Burn-out is a long-term problem, requiring sustainable solutions. Future research needs to develop and evaluate the effectiveness of evidence-based interventions to improve consultants' well-being. Trials of effectiveness need to present evidence that will persuade hospital management to invest in their consultants' well-being within the economic context of reduced budgets and limited PCC workforce.


Changing physical activity behavior in type 2 diabetes: a systematic review and meta-analysis of behavioral interventions.
Behavioral interventions targeting "free-living" physical activity (PA) and exercise that produce long-term glycemic control in adults with type 2 diabetes are warranted. However, little is known about how clinical teams should support adults with type 2 diabetes to achieve and sustain a physically active lifestyle. We conducted a systematic review of randomized controlled trials (RCTs) (published up to January 2012) to establish the effect of behavioral interventions (compared with usual care) on free-living PA/exercise, HbA(1c), and BMI in adults with type 2 diabetes. Study characteristics, methodological quality, practical strategies for increasing PA/exercise (taxonomy of behavior change techniques), and treatment fidelity strategies were captured using a data extraction form. Seventeen RCTs fulfilled the review criteria. Behavioural interventions showed statistically significant increases in objective (standardized mean difference [SMD] 0.45, 95% CI 0.21-0.68) and self-reported PA/exercise (SMD 0.79, 95% CI 0.59-0.98) including clinically significant improvements in HbA(1c) (weighted mean difference [WMD] -0.32%, 95% CI -0.44% to -0.21%) and BMI (WMD -1.05 kg/m(2), 95% CI -1.31 to -0.80). Few studies provided details of treatment fidelity strategies to monitor/improve provider training. Intervention features (e.g., specific behavior change techniques, interventions underpinned by behavior change theories/models, and use of ≥10 behaviour change techniques) moderated effectiveness of behavioral interventions. Behavioral interventions increased free-living PA/exercise and produced clinically significant improvements in long-term glucose control. Future studies should consider use of theory and multiple behavior change techniques associated with clinically significant improvements in HbA(1c), including structured training for care providers on the delivery of behavioural interventions.


Rapid Decline in Telestroke Consults in the Setting of COVID-19.
Background and Purpose: As coronavirus disease 2019 (COVID-19) continues to be a global pandemic, there is a growing body of evidence suggesting that incidence of diseases that require emergent care, particularly myocardial infarction and ischemic stroke, has declined rapidly. The objective of this study is to quantify our experience of telestroke (TS) consults at a large tertiary comprehensive stroke center during the COVID-19 pandemic. Methods: We retrospectively reviewed TS consults of patients presenting to our neuroscience network. Those with a confirmed diagnosis of acute ischemic stroke or transient ischemia attack were included. Data were compared from April 1, 2019, to June 30, 2020, which include consults prepandemic and during the crisis. Results: A total of 1,982 TS consults were provided in 1 year. Prepandemic, the mean monthly consults were 148. In April 2020, only 59 patients were seen (49% decline). Mobile stroke unit consults decreased by 72% in the same month. The 30-day moving average of patients seen per day was between five and six prepandemic declined to between two and three in April, and then began to uptrend during May. The mean percentage of patients receiving intravenous tissue plasminogen activator was 16% from April 2019 to March 2020 and increased to 31% in April 2020. The mean percentage of patients receiving endovascular therapy was 10% from April 2019 to March 2020 and increased to 19% in April 2020. Conclusions: At our large tertiary comprehensive stroke center, we observed a significant and rapid decline in TS consults during the COVID-19 pandemic. We cannot be certain of the reasons for the decline, but a fear of contracting coronavirus, social distancing, and isolation likely played a major role. Further research must be done to elucidate the etiology of this decline.


The strategic reference gene: an organismal theory of inclusive fitness.
How to define and use the concept of inclusive fitness is a contentious topic in evolutionary theory. Inclusive fitness can be used to calculate selection on a focal gene, but it is also applied to whole organisms. Individuals are then predicted to appear designed as if to maximize their inclusive fitness, provided that certain conditions are met (formally when interactions between individuals are 'additive'). Here we argue that applying the concept of inclusive fitness to organisms is justified under far broader conditions than previously shown, but only if it is appropriately defined. Specifically, we propose that organisms should maximize the sum of their offspring ( including any accrued due to the behaviour/phenotype of relatives), plus any effects on their relatives' offspring production, weighted by relatedness. By contrast, most theoreticians have argued that a focal individual's inclusive fitness should exclude any offspring accrued due to the behaviour of relatives. Our approach is based on the notion that long-term evolution follows the genome's 'majority interest' of building coherent bodies that are efficient 'vehicles' for gene propagation. A gene favoured by selection that reduces the propagation of unlinked genes at other loci (e.g. meiotic segregation distorters that lower sperm production) is eventually neutralized by counter-selection throughout the rest of the genome. Most phenotypes will therefore appear as if designed to maximize the propagation of any given gene in a focal individual and its relatives.


In Silico Analysis of the Effects of Point Mutations on α-Globin: Implications for α-Thalassemia.
Hemoglobinopathies are inherited diseases that impair the structure and function of the oxygen-carrying pigment hemoglobin (Hb). Adult Hb consists of two α and two β subunits. α-Thalassemia (α-thal) affects the genes that code for the α-globin chains, HBA1 and HBA2. Mutations can result in asymptomatic, mild or severe outcomes depending on several factors, such as mutation type, number of mutations and the location at which they occur. PredictSNP was used to estimate whether every possible single nucleotide polymorphism (SNP) would have a neutral or deleterious effect on the protein. These results were then used to create a plot of predicted tolerance to change for each residue in the protein. Tolerance to change was negatively correlated with the residue's sequence conservation score. The PredictSNP data were compared to clinical reports of 110 selected variants in the literature. There were 29 disagreements between the two data types. Some of these could be resolved by considering the role of the affected residue in binding other molecules. The three-dimensional structures of some of these variant proteins were modeled. These models helped explain variants which affect heme binding. We predict that where a point mutation alters a residue that is intolerant to change, is well conserved and or involved in interactions, it is likely to be associated with disease. Overall, the data from this study could be used alongside biochemical and clinical data to assess novel α-globin variants.


The Relationship between the Amount of Saturated Fat Intake and Semen Quality in Men.
Infertility in men is one of the current problems of human society. Some studies suggest that the metabolic status of a man, including cholesterol intake, closely correlates with sperm function. The aim of this study was to evaluate the correlation between saturated fat intake and semen quality among men referring to the Isfahan Fertility and Infertility Center, Iran. This cross-sectional study was conducted on all men who referred to the Isfahan Fertility and Infertility Center. The study population consisted of 120 men selected through simple random sampling. The data collection tool consisted of a two-part questionnaire including a demographic and anthropometric characteristics form and the Food Frequency Questionnaire (FFQ). The FFQ consists of 168 items that assess food and nutrient intake for 3 months. The reliability and validity of the instruments were confirmed in previous studies. Semen analysis was performed using computer-aided semen analysis (CASA) method. Descriptive statistics and logistic regression test were used to analyze the data. Results showed that the chances of having semen volume of higher than 1.5 ml (normal volume) increased by 27.5% for every 1 g increase in total fat (CI: 1.11-1.46) (P = 0.001) and reduced 38% for every 1 g increase in saturated fat (CI: 0.42-0.90, P = 0.010). No association was found between semen quality and intake of dietary fats. Based on the findings of this study and the prevalence of infertility in recent decades, changes in diet and saturated fatty acids intake may improve semen quality.


Level of Physical Activity and Knowledge about the Physical Activity Guidelines in a Group of Medical Residents from Puerto Rico.
Physicians who know about physical activity guidelines (PAG) and those who adhere to the PAG themselves may have a greater tendency to recommend physical activity (PA) to their patients. This study was aimed at evaluating the level of PA in a group of medical residents from Puerto Rico and to assess their knowledge regarding the PAG for adults. A total of 104 medical residents from Puerto Rico completed a selfadministered questionnaire designed to obtain standardized estimates of their PA and to determine their level of knowledge regarding the PAG. Results: Most of the medical residents (66.3%) declared that they did not have any knowledge of the existence of the PAG and that their residency programs had not provided any educational activities about the PAG (96.2%). The level of inactivity among medical residents was high; 41.35% reported not engaging in any PA during their leisure time. Most of the medical residents in this group from Puerto Rico did not know about the PAG and many of them did not engage in PA. As a means of improving patient care, medical residents from Puerto Rico might benefit if their programs implemented educational activities aimed at increasing knowledge of both PA and the PAG.


Biochemical markers for prediction of chemotherapy-induced cardiotoxicity: systematic review of the literature and recommendations for use.
Chemotherapy is a well-established therapeutic approach for several malignancies, but its clinical efficacy is often limited by its related cardiotoxicity, which leads to cardiomyopathy, possibly evolving into heart failure. To detect cardiac damage, the adopted diagnostic approach is the estimation of left ventricular ejection fraction by echocardiography. This approach shows low sensitivity toward early prediction of cardiomyopathy, when the possibilities of appropriate treatments could still improve the patient's outcome. Cardiac troponins, however, show high diagnostic efficacy as early as 3 months before the clinical onset of cardiomyopathy. The increase in their concentrations is correlated with disease severity and may predict the new onset of major cardiac events during follow-up. Negative troponin concentrations may identify patients with a very low risk of cardiomyopathy (negative predictive value, 99%). Concerning cardiac natriuretic peptides, definitive evidence in regard to a diagnostic or prognostic role in predicting chemotherapy-induced cardiomyopathy is still lacking.


Regional cerebrovascular oxygen saturation measured by optical spectroscopy in humans.
Regional cerebrovascular oxygen saturation, a quantitative measure of hemoglobin saturation in the combined arterial, venous, and microcirculatory compartments of the brain, can be measured noninvasively with near infrared spectroscopy. We assessed the sensitivity of this aggregate saturation to cerebral hypoxia during transient cerebral hypoxic hypoxia in seven human subjects. Regional cerebrovascular oxygen saturation measured over the middle frontal gyrus and analog electroencephalogram were recorded. We compared the time to achieve two end points: the earliest paroxysmal burst of theta-delta background slowing and a cerebrovascular oxygen saturation of less than 55%. Saturation fell below 55% prior to the electroencephalographic change (p less than 0.05). In a related effort, we also compared spectroscopically measured regional cerebrovascular oxygen saturation with an estimate of this value calculated from arterial and cerebral mixed venous saturation in nine patients. A positive linear relation (n = 68, R2 = 0.55, s = 4.2) was noted.


Iron accelerates hemoglobin oxidation increasing mortality in vascular diseased guinea pigs following transfusion of stored blood.
Non-transferrin-bound iron (NTBI) and free hemoglobin (Hb) accumulate in circulation following stored RBC transfusions. This study investigated transfusion, vascular disease, and mortality in guinea pigs after stored RBC transfusion alone and following cotransfusion with apo-transferrin (apo-Tf) and haptoglobin (Hp). The effects of RBC exchange transfusion dose (1, 3, and 9 units), storage period (14 days), and mortality were evaluated in guinea pigs with a vascular disease phenotype. Seven-day mortality and the interaction between iron and Hb as cocontributors to adverse outcome were studied. Concentrations of iron and free Hb were greatest after transfusion with 9 units of stored RBCs compared with fresh RBCs or stored RBCs at 1- and 3-unit volumes. Nine units of stored RBCs led to mortality in vascular diseased animals, but not normal animals. One and 3 units of stored RBCs did not cause a mortality effect, suggesting the concomitant relevance of NTBI and Hb on outcome. Cotransfusion with apo-Tf or Hp restored survival to 100% following 9-unit RBC transfusions in vascular diseased animals. Our data suggest that increases in plasma NTBI and Hb contribute to vascular disease-associated mortality through iron-enhanced Hb oxidation and enhanced tissue injury.


Effect of tissue permeability and drug diffusion anisotropy on convection-enhanced delivery.
Although convection-enhanced delivery (CED) can successfully facilitate a bypass of the blood brain barrier, its treatment efficacy remains highly limited in clinic. This can be partially attributed to the brain anisotropic characteristics that lead to the difficulties in controlling the drug spatial distribution. Here, the responses of six different drugs to the tissue anisotropy are examined through a parametric study performed using a multiphysics model, which considers interstitial fluid flow, tissue deformation and interlinked drug transport processes in CED. The delivery outcomes are evaluated in terms of the penetration depth and delivery volume for effective therapy. Simulation results demonstrate that the effective penetration depth in a given direction can be improved with the increase of the corresponding component of anisotropic characteristics. The anisotropic tissue permeability could only reshape the drug distribution in space but has limited contribution to the total effective delivery volume. On the other hand, drugs respond in different ways to the anisotropic diffusivity. The large delivery volumes of fluorouracil, carmustine, cisplatin and doxorubicin could be achieved in relatively isotropic tissue, while paclitaxel and methotrexate are able to cover enlarged regions into anisotropic tissues. Results obtained from this study serve as a guide for the design of CED treatments.